Presentation: Pregnancy at risk of Marfan syndrome

A woman has undergone pre-pregnancy investigations because her brother and father died suddenly from abdominal aortic aneurysm. The investigations have demonstrated a dilated aortic root at 40mm, and genomic testing has revealed a genetic change consistent with Marfan syndrome. The woman now presents in pregnancy with questions about genomic testing and the risk to her unborn baby.

Consider genomic testing if:

• there is a confirmed family history of Marfan syndrome (either clinically diagnosed or confirmed via a genomic test);
• there is a suspected family history of Marfan syndrome; or
• fetal echocardiogram findings are suggestive of prenatal Marfan syndrome (such as aortic root dilatation).

• Collect a detailed family and personal history from the couple.
• Refer to a clinical genetics department for review by a clinical geneticist or genetic counsellor.
  • The clinical genetics team will review the National Genomic Test Directory to identify which tests the woman is eligible for.
• For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For a pregnancy in which there is a known maternal and/or paternal disease-causing variant, prenatal testing is available.
  • If the mother is affected, invasive testing is usually offered.
  • If the father is affected, non-invasive prenatal diagnosis (NIPD) may be an available option (usually early within the first trimester).
  • Where there is a known variant, preimplantation genetic testing may be available in a future pregnancy.
• Where there is a suspicion of Marfan syndrome in a family member or either parent, but no prior genomic test result is available, the relevant test is:
  • R125 Thoracic aortic aneurysm or dissection. This can be requested in the presence of features of Marfan syndrome giving a systemic Ghent score of ≥7, following assessment by a clinical geneticist or a specialist with expertise in aortopathy.
  • If a pathogenic (disease-causing) genetic variant is found, testing can be offered to blood relatives of the affected person.
• Where clinical features in the fetus are suspicious for Marfan syndrome:
  • it should be noted that prenatal Marfan syndrome is challenging to diagnose from antenatal scan findings, especially without a family history;
  • you should consider urgent investigations, reflecting the critical need for information to guide pregnancy management (in accordance with parental choice); and
  • you should discuss the most appropriate genomic testing available with your local clinical genetics unit and Genomic Laboratory Hub (GLH). This may include the following.
    • R125 Thoracic aortic aneurysm or dissection: This includes Marfan syndrome and other related disorders. If R125 cannot be performed urgently or is non-diagnostic, additional genomic testing, such as R21, may be required.
    • R21 Fetal anomalies with a likely genetic cause: Unless clinical information and/or initial results indicate otherwise, R21 requests will process:
      • R21.1 Genome-wide common aneuploidy testing;
      • R21.2 Fetal anomalies whole exome sequencing or large panel sequencing; and
      • R21.3 Genome-wide microarray.
• None of the tests outlined above use whole genome sequencing, so you should use your local GLH test order form and consent (record of discussion) form.
• Parental samples may be needed for interpretation of the proband’s result. Parental samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed.
• For R21 Fetal anomalies with a likely genetic cause, you will need to:
  • ensure that the required multidisciplinary discussions have taken place, including fetal medicine, clinical genetics and the regional specialist R21 laboratory, and that there is an agreement that R21 can be offered;
  • inform your local laboratory of the plan for R21 testing, so that they can arrange the necessary exports to the specialist R21 laboratories in a timely fashion;
  • fill in the R21-specific test order form;
  • take informed consent for both parents, documented on R21-specific record of discussion forms;
  • send blood samples for both parents to the local laboratory (if only one parent is available, let the lab know – testing can still proceed, but there will be a small reduction in diagnostic yield); and
  • arrange and send a chorionic villus sample or amniocentesis sample for the fetus.
• Note that, in Scotland, referral to clinical genetics is required for consideration of rapid prenatal exome testing.
• For NIPD, a blood sample in a Streck tube is required. For invasive tests, an amniocentesis or chorionic villus sample or fetal blood sample (in an EDTA tube) is required, as well as a sample from the mother to test for maternal cell contamination. For many tests, parental samples are also needed or are helpful. For more information about different sample types, see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• GeneReviews: FBN1-related Marfan syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: National Genomic Test Directory Clinical Indication R21 Rapid prenatal exome sequencing test request (PDF, two pages)
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: Record of discussion regarding prenatal exome sequencing (PDF, two pages)

For patients

• NHS Health A to Z: Marfan syndrome
• NHS North Thames and NHS West Midlands, Oxford and Wessex Genomic Laboratory Hubs: Information on prenatal exome sequencing for parents (PDF, two pages)
• The Marfan Foundation